Compositions and processes for accelerated wound healing using novel fibrous webbings

ABSTRACT

The present invention provides a multilayer bandage, having a webbing for contacting a wound and a first membrane that has at least one water-insoluble polymer and is water-impervious. The present invention further provides methods for making the multilayer bandage, methods of using the multilayer bandage for accelerated wound healing, and kits having compositions of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of provisional application Ser. No.60/640,896, filed Dec. 30, 2004 and German patent application DE 10 2004063 599.4, filed Dec. 30, 2004, the disclosures of which areincorporated in their entirety herein by reference.

FIELD OF THE INVENTION

The present invention relates to a spun-bonded or fibrous webbing-basedmultilayer bandage useful for accelerated wound healing.

BACKGROUND OF THE INVENTION

A moist wound closure is known in the prior art (Blank, Wundversorgungund Verbandwechsel, Kohlhammer-Verlag, Stuttgart, 2001; Stalick, Br JNurs 2004, 13(18):1107-1109; Metzger, Home Health Nurse 2004,22(9):586-590). The problem with this type of wound treatment is thatthe contact medium, for example, bandage gauze, plaster, etc., mayconcrete with the wound during the heal-over process. As the contactmedium is subsequently removed, the wound is frequently reopened, whichresults in the destruction and removal of the newly generated tissue.Clearly, the wound healing process is unnecessarily slowed down as aresult. When using wound dressing pads that do not adhere to the wound,thereby preventing concretion of the dressing pad with the wound, thewound defect nevertheless lacks a support and guide structure to whichthe newly formed tissue is oriented and on which it can grow. Thiscondition leads, particularly in the case of deep wounds, to theformation of a substantive defect. A further consequence is theformation of unnecessary and undesirable scarring. In clinical practice,this problem extends to all wounds that involve not only the epidermis,but the corium as well and, where applicable, the subcutis (so-called“deep” wounds), and requires reconstitution of both the epidermallayers, the corium and, where applicable, the subcutis.

The thickness of the epidermis (upper dermal layer) normally varies and,depending upon location, can measure from 0.03 to 4 mm. Age and sexinfluence the thickness of the epidermis as well. The epidermis containsno blood vessels, and is formed from keratinocytes. Keratinocytes arehorn cells which possess a cell nucleus and which produce keraticmaterial, or keratin. Keratin is water repellant and imparts resiliencyto the skin tissue.

The underlying corium is a resilient layer of skin tissue containing ahigh ratio of loosely intertwining connective tissue. This layer mayalso vary in thickness, depending upon location. On the penis andeyelids the corium is a mere 0.3 mm in thickness, whereas on the handsand soles of the feet, it can measure as much as 2.4 mm.

The aforementioned problems concern both slow-healing or completelynon-healing wounds, such as the chronic diabetic-neuropathic ulcus,ulcus cruris, decubitus wounds and secondary healing wounds, as well asnon-irritating, primary healing wounds (for example, ablativelacerations, excoriations (in which tissue has been grazed and therebyremoved from the wound), and split thickness removal sites.

Biologically degradable and/or resorbable fiber structures (silicongel-fibers and fiber structures) are known from German patentapplication DE-C 196 09 551 (incorporated herein in its entirety byreference). These fiber structures are obtained by drawing fibers from aspun composition and optionally drying them. The spun compositioncontains one or more partially or completely hydrolytically condensedsilicon compounds derived by hydrolytic condensation of monomers of thegeneral formula SiX₄, wherein residues X₁, X₂, X₃, and X₄ are identicalor different and are either hydroxyl, hydrogen, halogen, amino, alkoxy,alkyloxy, alkylcarbonyl or alkoxycarbonyl, or are derived fromalkyl-residues and can be interrupted by one or more oxygen atoms,sulfur atoms or amino groups.

Methods for producing a skin tissue graft and/or cells, tissues andorgans based on the aforementioned fibrous structures are also knownfrom WO 01/42428 and EP-A 01 262 542. PCT publication WO 01/42428(incorporated herein in its entirety by reference) describes a methodfor producing a skin tissue graft, in particular a skin tissueautograft, wherein skin tissue cells are placed on the surface of aculture medium and allowed to grow. This method is characterized in thata surface element, in particular an aforementioned biocompatible,biodegradable and/or bioresorbable fiber, webbing or fabric is placed onthe culture medium along with the skin tissue cells. The fibers of thesurface element have a diameter ranging from about 5 μm to about 20 μm.The term “about” as used herein means approximately and refers to arange of values of plus or minus 10% of a specified value. For example,the phrase “about 20 μm” includes plus or minus 10% of 20 μm, or from 18μm to 22 μm.

EP patent application EP-A 01 262 542 (incorporated herein in itsentirety by reference) describes a method for the in vitro production ofcells, tissues and organs, in which the fiber matrix (see, DE-C 196 09511) functions as a cell support substance and/or guide structure forthe extra-cellular matrix formed by the cells, and makes it possible forthe cells to find a spatial orientation which permits the cells tomultiply and/or to achieve their genetically determined differentiation.

Realizing the limitations and shortcomings of the prior art describedabove and the need for a better contact medium for accelerated woundhealing, the present invention describes the developing and preparing ofa contact medium, in its broadest sense a dressing, gauze, plaster,capable of contacting a wound, but without having to tolerate theaforementioned disadvantages such as concretion of the contact mediumand the wound, destruction of newly formed tissue, unnecessarily slowwound healing, excessive scarring, and defective (healing) growth. Thus,the present invention provides a contact medium, in particular amultilayer bandage, for which it is possible to leave the contact mediumin or on a moist wound and to leave it in place even after the wound hashealed over, so as to not disrupt the healing process, to provide aguide structure for the newly forming tissue, and lastly to prevent theformation of scarring.

SUMMARY OF THE INVENTION

While the present invention may be embodied in many different forms,several specific embodiments are discussed herein with the understandingthat the present disclosure is to be considered only as anexemplification of the principles of the invention, and it is notintended to limit the invention to the embodiments illustrated.

The present invention offers a solution to the above described problem.One aspect this invention describes a novel use of fibers disclosed inGerman patent publication DE-C 196 09 551 to produce a multilayerbandage for accelerated wound healing. The fibers are processed to forma webbing which may then be combined with many conventional bandagingmeans, including, but not limited to, bandaging means that are applieddirectly onto or in a wound. Hereinafter, this combination is referredto as a multilayer bandage, even where reference is made not to atypical bandage but rather to a plaster or compress or the like.

Thus, in a preferred embodiment of the present invention, a multilayerbandage is provided which comprises (i) a webbing for placement indirect contact with a wound having a periphery, and (ii) a firstmembrane comprising at least one water-insoluble polymer, wherein thefirst membrane is water-impervious. The first membrane may furthercomprise an adhesive portion, wherein the adhesive portion adheres toskin tissue at the wound periphery. Alternatively the first membranedoes not comprise an adhesive portion and bonds with an adhesive whichis applied to the skin tissue at the wound periphery. Between the firstmembrane and the webbing either no bond or a loose, frangible adhesivebond exists.

In one embodiment of the present invention, the water-insoluble polymerof the first membrane is selected from the group consisting ofpolypropylene (PP), polyvinylchloride (PVC) and polyurethane (PU).

In one embodiment of the present invention, the first membrane is aself-adhesive hydropolymer.

In a preferred embodiment of the present invention, the webbing may alsohave a biologically degradable or resorbable fiber structure. In anotherpreferred embodiment of the present invention, the webbing is a fibrouswebbing.

A preferred webbing of the present invention is a spun-bonded webbingthat comprises at least one partially or completely hydrolyticallycondensed silicon compound. This fiber structure can be obtained bydrawing threads from a spun composition wherein the spun compositioncomprises the at least one partially or completely hydrolyticallycondensed silicon compound. The silicon compound comprises a monomer ofthe formula SiX₄. SiX₄ is a tetravalent compound comprising residues X₁,X₂, X₃, and X₄. In one embodiment, residues X₁, X₂, X₃, and X₄ areidentical. In another embodiment, residues X₁, X₂, X₃, and X₄ aredifferent. In a preferred embodiment, residues X₁, X₂, X₃, and X₄ areindependently selected from the group consisting of hydroxyl, hydrogen,halogen, amino, alkoxy, alkyloxy, alkylcarbonyl and alkoxycarbonyl. Inanother embodiment, residues X₁, X₂, X₃, and X₄ are derived from analkyl and can be interrupted by an oxygen atom, a sulfur atom or anamino group. In a preferred embodiment of the present invention,residues X₁, X₂, X₃, and X₄ are ethyl.

The invention further provides a multilayer bandage wherein the webbingcomprises an organic compound selected from the group consisting of anucleotide, an amino acid and polymers thereof. A preferred organiccompound is a morphogenic factor selected from the group consisting of asteroid, a cytokine, an interleukin, a bone morphogenetic protein, anantibody, TNF-α, TGF-β½, IGF, PDGF, and EGF.

In another preferred embodiment of the present invention, a multilayerbandage comprises (i) a webbing for placement in direct contact with awound having a periphery, and (ii) a first membrane comprising at leastone water-insoluble polymer, wherein the first membrane iswater-impervious; and (iii) a second membrane comprising at least onewater-soluble polymer and wherein the second membrane is disposedbetween the first membrane and the webbing. In a preferred embodiment,the water-soluble polymer is carboxymethylcellulose.

In one embodiment of the present invention, a loose, frangible adhesivebond exists between the second membrane and the webbing. In anotherembodiment, no adhesive bond exists between the second membrane and thewebbing.

In one embodiment of the present invention, a bond exists between thefirst membrane and the second membrane. This bond can be a loose,frangible adhesive bond or a stable, non-frangible adhesive bond. In yetanother embodiment, no bond exists between the first membrane and thesecond membrane.

In another preferred embodiment of the present invention, a multilayerbandage comprises (i) a webbing for placement in direct contact with awound having a periphery; (ii) a first membrane comprising at least onewater-insoluble polymer, wherein the first membrane is water-impervious;and (iii) a dressing selected from the group consisting of an alginate,a collagen sponge, a polyurethane foam, a polyurethane foam pad, ahydrocolloid, a hydrogel and a hydropolymer, and wherein the dressing isdisposed between the webbing and the first membrane. In one embodiment,a loose, frangible adhesive bond exists between the dressing and thewebbing. In another embodiment, no adhesive bond exists between thedressing and the webbing.

In other preferred embodiments of the present invention, (i) no adhesivebond (ii) a loose, frangible adhesive bond or a (iii) stable,non-frangible adhesive bond exists between the dressing and the firstmembrane.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a multilayer bandage in accordance with the presentinvention, fitted into a wound. 1, webbing; 2, second membrane; 3, firstmembrane; 4, wound.

FIG. 2 shows a sketch of a hole-type nozzle in an injector plate.

FIG. 3 shows a schematic illustration of the galette-system and the airconditioning unit.

FIG. 4 shows adhesion of cells to the surface of a fiber (SEM analysis).FIGS. 4A and 4B show a SiX₄-fiber of the present invention withoutcells. FIGS. 4C and 4D show a SiX₄-fiber of the present invention withcells and their excellent adhesive and spreading properties. FIGS. 4Eand 4F show a collagen fiber with cells, whose morphology is difficultto ascertain due to the course nature of the collagen matrix.

FIG. 5 shows the shape and shrink resistance of an SiX₄ fiber of thepresent invention compared with collagen fibers and PGA fibers. The lefthand column, from top to bottom, shows a collagen fiber, a PGA fiber anda SiX₄ fiber of the present invention prior to cell cultivation. Theright hand column, top to bottom, shows a collagen fiber, a PGA fiberand a SiX₄ fiber of the present invention four weeks after the start ofcell cultivation.

FIG. 6 shows the metabolic activity of cells (dermal fibroblasts),measured by fluorescence using the alamarBlue™ Assay, after 1, 2 and 4weeks of cultivation with a collagen fiber (Collagen), a PGA fiber(PGA), and a SiX₄ fiber of the present invention (SIX) and, for purposesof comparison, without fibers (Cells).

DETAILED DESCRIPTION OF THE INVENTION

A. Manufacturing Fibers, Webbings, Membranes and Multilayer Bandages

The present invention offers a solution to the problem described above.The present invention describes a novel use of fibers (as described inGerman patent publication DE-C 196 09 551) for producing and using amultilayer bandage for accelerated wound healing. The aforementionedfibers can be formed into a webbing and the webbing when brought intocontact with a wound, accelerates wound healing. As used herein,“contact” or “contacting” means to place in direct physical association.The webbing may then be combined with all conventional dressings, inparticular with those that are applied directly on or in a wound, i.e.,brought into direct contact with the wound. This combination is referredto hereinafter as a multilayer bandage, even where reference is made notto a conventional bandage, but rather to a plaster, compress or thelike. Thus, in a preferred embodiment of the present invention, amultilayer bandage comprises (i) a webbing which can be placed in directcontact with a wound having a periphery, and (ii) a first membranecomprising at least one water-insoluble polymer, wherein the firstmembrane is water-impervious. In one preferred embodiment, the firstmembrane is an adhesive plaster (adhesive bandage) as further describedherein.

As previously described, moist webbings can be produced from silicon-gelfibers or fibrous structures (DE-C 196 09 551). Thus, the term “webbing”as used herein refers to a three-dimensional structure or arrangementmade of fibers or fibrous structures, for example, silicon-gel fibers.The general chemical formula relating to the monomer unit isSiO_(2-x)OH_(x) and the one relating to the polymer isSi_(n)(OH)_(2-x)O_(2n-x), wherein x=0-1, that is x can be any numberbetween 0 and 1 and including 0 and 1. For example, in one embodiment ofthe present invention (see further below), x is between 0.1 and 0.2 andincludes 0.1 and 0.2. Webbings of the latter formula, according to thepresent invention, can be placed in a wound as support and guidestructure and thus in direct contact with the tissue. New tissue formsat the webbing that to some extent determines the growth direction ofthe newly formed tissue. With respect to webbings, a differentiation ismade between fibrous webbings and spun-bonded webbings. In particular,spun-bonded webbings, made of continuous single fibers, threads orsingle filaments, are advantageous for 3-D applications, while fibrouswebbings are particularly suited to 2-D applications. The terms “singlefiber,” “thread” or “single filament” herein are used interchangeably.

A method for producing single fibers or single filaments is described inthe German patent application DE-C 196 09 551 (incorporated in itsentirety by reference). Here, one of skill in the art will recognize andappreciate that numerous parameters, such as temperature, pressure,molar ratio of individual components, chemical nature of reactants ofthe solvent or of catalysts may be varied to produce particularlysuitable fibers and webbings, for example, webbings having high or lowbiodegradability and bioresorbability.

The method set forth in DE-C 196 09 551 is described once again insomewhat greater detail. In a preferred embodiment of the presentinvention, TEOS (tetraethoxysilane) is used as silane in asol-gel-process. Likewise, all of the silanes or mixtures of at leasttwo of the latter described in DE-C 196 09 551 can be used in amultilayer bandage of the present invention. Silanes useful for themethods and compositions of the present invention are commerciallyavailable or can be synthesized using methods known in the art (“Chemieund Technologie der Silicone,” W. Noll, Verlag Chemie, Weinheim, 1968)and include, but are not limited to, for example, Si(OMe)₄,Si(OMe)₃(OEt), Si(OMe)₂(OEt)₂, Si(OMe)(OEt)₃, Si(OEt)₄, Si(O-i-Pr)₄,Si(OMe)₃(O-i-Pr), Si(OMe)₂(O-i-Pr)₂, Si(OMe)(O-i-Pr)₃, Si(OEt)₃(O-i-Pr),Si(OEt)₂(O-i-Pr)₂, Si(OEt)(O-i-Pr)₃, Si(O-n-Pr)₄, Si(OMe)₃(O-n-Pr),Si(OMe)₂(O-n-Pr)₂, Si(OMe)(O-n-Pr)₃, Si(OEt)₃(O-n-Pr),Si(OEt)₂(O-n-Pr)₂, Si(OEt)(O-n-Pr)₃, Si(O-i-Pr)₃(O-n-Pr),Si(O-i-Pr)₂(O-n-Pr)₂, Si(O-i-Pr)(O-n-Pr)₃, Si(OMe)(OEt)₂(O-i-Pr),Si(OMe)(OEt)₂(O-n-Pr), Si(OMe)(OEt)(O-i-Pr)₂, Si(OMe)(OEt)(O-n-Pr)₂,Si(OMe)(O-i-Pr)₂(O-n-Pr), and Si(OMe)(O-i-Pr)(O-n-Pr)₂.

In the presence of an aqueous-alcohol solution (preferably anethanol/water mixture according to the present invention) which servesboth as a solvent (ethanol or ethanol/water) and also as a reactionpartner (water) for the hydrolytic condensation, a condensation productof a suitable degree of condensation is produced at ambient temperatureor at slightly reduced temperature (from about 12° C. to about 15° C.).A preferred catalyst for the condensation is an organic acid including,but not limited to, for example, citric acid, succinic acid and tartaricacid. Such acids adjust the pH of the reaction mixture to approximately3-4. Preferably, the condensation reaction is performed at a pH below 7.Undesirable particle formation or gel-like structures have been observedat pH>7. Thus, in a preferred embodiment of the present invention, thepH of the condensation reaction is <7, preferably the pH is <6, morepreferred the pH is <5, even more preferred, the pH is <4. Particularlypreferred is a pH range from about 3 to about 4.

The condensation product is rendered viscous by filtration and removalof the solvent (see DE-C 196 09 551). The product can be stored for acertain time (several hours up to a few months) at temperatures below 0°C. upon formation of a so-called spinning sol (a spun composition, whichis the product of the polymerization/condensation reaction). This ispossible because at temperatures below 0° C. condensation occurs onlyvery slowly.

In another preferred embodiment of the invention, a spinning sol has asolids content of approximately 10%, i.e. the solvent ratio isapproximately 90%. Solids in this context refers to the condensationproducts, such as oligomers and oligomeric structures. Also preferred inaccordance with the present invention is a time period of from about 2-3days from the onset of the condensation reaction until the spinning solis obtained.

In one embodiment of the present invention, a spinning sol is added to apre-cooled (<0° C.) pressurized container, from which it is forced outunder pressure through small nozzles in the form of long, non-tearing,or tear resistant threads. The threads measure approximately 10 to 100μm in diameter and up to several meters in length (for example, 3-5meters), depending on the size of the nozzles. As the threads are wound,their length may optionally by extended and their diameter furtherreduced as a result of pulling (stretching) during take up (optionallyin an aqueous-alcohol atmosphere).

The threads can be wound at a speed of 100-1000 m/min, preferably at aspeed of approximately 200 m/min. In one embodiment, the resultant spunthreads are then passed over a roller and interlaced on a carrier strip.The threads on the carrier strip may be exposed to varying temperaturesas a result of the carrier strip migrating across differing temperaturezones at an operating speed of 1-10 cm/min. Thus, over the course of acondensation reaction it is possible to adjust by any desirable numberthe OH-groups remaining in the fibers (that is, the biodegradability andbioresorbability of the fibers). The threads can be abruptly cooled to−35° C. in the form of gel strands on the carrier strip.

In a preferred embodiment of the present invention, the interlacedthreads (continuous or endless fibers) are compressed to form aspun-bonded webbing or a fibrous webbing. Compression can be performedby means of a pressure roller. In another aspect, embroidering looms(pressure rollers with needles) can be employed. The up and down motionof the needles defines a fulling process that imparts added strength tothe webbing. The pressure imparted by the roller with and withoutneedles is freely adjustable. In a preferred embodiment of the presentinvention, the compression force is from about 1 MPa to about 10 MPa.Next, the webbing is thermally treated, wherein temperatures vary withina range of from about −35° C. to about +65° C. Preferred is atemperature of below −5° C., more preferred a temperature of below −20°C.

Such thermal treatment yields a structurally rigid sheet simultaneouslyexhibiting a sufficient number of silanol-, that is, uncondensedOH-groups, in the webbing. The number of uncondensed OH-groupsdetermines the degree of (bio)resorbability: the more uncondensedOH-groups present, the greater the (bio)resorbability. Conversely, thefewer uncondensed OH-groups, the lower the (bio)resorbability. Byvarying the retention times at different temperatures it is possible toadjust specifically the number of OH-groups. In a preferred embodimentof the present invention, the fibers of the webbing have approximatelyone OH-group per 5-10 Si-atoms, which means in the formula above for themonomer unit SiO_(2-x)OH_(x), that x=0.1-0.2.

In a further, optional step, the webbing is thermally treated at atemperature of 50° C. or to a temperature above 50° C. in order toremove, to the extent desirable, most though not all of any remainingwater and ethanol. This can be done, for example, from the solvent, aswell as from the remains of the starting silane, in particular in thecase of TEOS as starting silane. Thus, in a preferred embodiment of thepresent invention, a webbing, in particular a spun-bonded webbing,retains a sufficient amount of residual moisture. Thereby it is possibleto stabilize the thermodynamically unfavorable gel state (fibers withuncondensed OH-groups in the webbing) compared to the SiO₂ state (fiberswithout uncondensed OH groups, i.e. glass fibers, in the webbing), whichis more stable at room temperature. A spun-bonded webbing produced inthis manner retains its gel state for a period of several months whenenclosed in an airtight packaging or container. It has been found thatthe presence of residual ethanol, but also that of water is particularlyadvantageous in this regard. This may be because condensation towardsSiO₂ ceases to continue in a (saturated) ethanol-atmosphere. This caneven be reversed leading to the bioresorbability of the fibers.

The method described above is used in the production of a spun-bondedwebbing. A fibrous webbing, sometimes also referred to as needle-punchwebbing, may also be produced in this manner. As part of this process,the fibers are cut into pieces following the spinning step. Theresultant staple fibers are 0.1-10 cm in length. Next, the staple fibersare cast onto a carrier strip, compressed, needle punched and subjectedto thermal treatment of the type described above. Unlike spun-bondedwebbings, fibrous webbings have no characteristic 3D-structure. Hencethe latter are frequently employed in 2D applications, including, butnot limited to, for example, surface wounds in the upper epidermalregion. Thus, in a preferred embodiment of the present invention, afibrous webbing is used in the treatment of a superficial wound (i.e., awound on the surface), including, but not limited to, wounds in theupper epidermal region. In general, it can be noted that at the fiberlevel, fibrous webbings exhibit generally greater stabilities and arethus better suited at mechanically loaded sites, for example, preferredin treating skin tissue wounds, rather than muscle wounds.

The fiber production as described above is carried out by way of asol-gel process on a machine that may have the following dimensions:approximately 5 m long, approximately 2 m wide and approximately 6 mhigh. The weight of the machine in the area below the spin towergenerates a pressure ranging from about 850 to about 1,000 kg/m².Machine dimensions may, however, deviate considerably from those citedherein depending upon the equipment and productive capacity. Forproduction, the machine requires cool water circulation with an adequatewater supply and preferably a high-voltage connection.

The machine as described above is used for producing the fibers.Depending on the desired product, one or more additional processes maybe added to the machine, such as a loom for producing a webbing.

Fibers of the present invention can also be produced on anair-conditioned spinning machine (FIG. 3). The air-conditioned spinningmachine is supplied with air by an ambient air-driven air conditioningunit. The air has a specific temperature and humidity. Preferably, thetemperature of the air ranges from about 10° C. to about 40° C., mostpreferred the temperature is about 20° C. An example of such a unit isthe climate testing cabinet manufactured by Weiss Umwelttechnik GmbH,model designation SB22/160/40-UKA, which was re-equipped by WeissUmwelttechnik for recirculating air. To prevent disruptions caused byconvection in the recirculating air, a tube 300 mm in diameter with 3 mmrounded holes is inserted into an insulated spinning tower 2 m in lengthand having an outer diameter of 680 mm. The spin tower is connected to abox within which the winding devices for the aforementioned continuousfibers or filaments are disposed. For purposes of adequate insulation,the panes of the box are made of window glass (24 mm thickness) having aK-value of 1.1. The air exiting the box is fed back to the airconditioning unit and reconditioned. The climate measuring sensor is notthe interior space of the unit, but rather an external sensor disposedin the spin shaft. The air-conditioning unit is controlled (optionallyalso manually) by link-up to a PC supplied with the appropriatemanufacturer software. Temperature and humidity programs, in addition toall other requisite unit settings, may be preset with the use of thePCC_WIN, Version 1.05 software. During the spinning operation a plottermay be used to display temperature and humidity on a time controlledbasis. An additional temperature sensor has been attached for monitoringthe outside temperature. This value is also recorded digitally. In theevent the spinning machine is provided with process control engineering,all essential measuring points are fitted with an analog output.

The incoming and outgoing air connections between the air conditioningunit and the spin tower or box consist of flexible, double-insulatedhoses with an interior diameter of 100 mm (exterior diameter: 250 mm).Each of the connectors is encased in Armaflex. Since potentially ethanolmay be released from the spun composition during the spinning phase,which can accumulate within the closed loop of the air conditioner, spintower and box, the machine has been equipped with a gas hazard warningdevice manufactured by GfG Gesellschaft flir Geratebau. One measurementtransducer each, calibrated to ethanol, model designation MWG 0238 EX,has been mounted in the box directly adjacent the motors, and in thetesting chamber of the recirculated air conditioning unit. An evaluationunit (GMA 100-BG) sounds an initial alarm if the concentration ofethanol in the chamber air reaches 25% of the lower explosive limit ofthe ethanol, and a second alarm if the concentration reaches 50% of thelower explosive limit. An alarm is also triggered in the event themeasurement transducer experiences an outage or malfunctions.

Disposed at the upper end of the spinning tower is a slide gate valveand intermediate flange with three potential points of connection towhich the double-walled, outwardly insulated spinning head is mounted.According to the test report on pressure testing the spinning head issuited to a pressure of up to 50 bar (5×10⁶ Pa). At an inner diameter of45 mm, the spinning head holds 0.33 liters of spun composition.

An injector plate is mounted to the spinning head from below. The plate,measuring 89 mm in diameter, has an inset 1.5 mm in depth into which astainless steel mesh encased in aluminum is inserted. The wire screen isbi-layered, the first layer having a mesh size of 80 μm.

A second support layer has a mesh size of 315 μm. The aluminum casingaround the wire mesh is designed so that as the netting is placed in theinjector plate, the former protrudes by 0.5 mm. If the plate with themesh is screwed onto the spinning head at 15 Nm, the compressed A1-ringthen supplies the requisite seal between the spinning head and plate.Seven and 19-hole injector plates were used. A hole is pre-bored towidth of 3.0 mm, the hole diameter being 0.15 mm. A capillary length of0.45 mm results in an L/D ratio of 3. A sketch of a hole-type nozzle inan injector plate is shown in FIG. 2.

The double-walled spinning head is temperature-equalized with the aid ofa thermostat manufactured by LAUDA (model designation RE 112), in whichthe feed and exhaust hoses are insulated with Armaflex.

Inserted into the three intermediate flange connections between thespinning head and tower are viewing windows which permit observation ofthe threads exiting the nozzles. In designing a device for depositingfilaments, consideration was also given, apart from a winding unit, tothe possibility of fiber deposition by way of a gas feed nozzle. Forthis purpose a system for warping the filaments was constructed of 2galettes 159 mm and 220 mm in length, respectively, in which the reargalette is angled 8° with respect to the front galette. The power driveis a motor-tacho-combination (model designation S4.3 G60) and gearing(model designation 381, 3.71:1) manufactured by Faulhaber. Therotational speed of the first galette is automatically transferred tothe second galette.

Using a warp regulator the rotation of the second galette may beincreased by up to 10%. A third galette serves as a winder and can beoperated independently of the warp unit. The former is composed of amandrel, also actuated by a Faulhaber motor-tacho combination, to theformer of which a cardboard roller may be clamped. The cardboard rolleris composed of five individual circular segments that are springdesigned and bound together to form a circular diameter of 159 mm. Whenreleased, the diameter of the roller is reduced from 159 mm to 143 mm. ATeflon film is glued to the exterior of the five segments.

The third galette is mounted on a charging unit manufactured byIsel-Automation. Using a stepping motor, model designation 160 MCM, thewinding apparatus is chargeable to a length of 500 mm. The chargingfrequency from the forward and return traverse of the unit may beadjusted to values ranging from 2 to 16 min⁻¹, and a second control unitcan be used to move the galette manually. A control unit for the galettemotors and the charging stepping motor were manufactured fromControllers (IT 142-C), a single-axle-stepping motor control withadapter card and a control card (UMS 6) from Isel-Automation. Aschematic illustration of the galette-system and the air conditioningunit is shown in FIG. 3.

Hereinafter, unless stated differently, the term webbing is usedsynonymously for spun-bonded webbing and fibrous webbing. In a preferredembodiment of the present invention, a webbing is used to contact awound having a periphery. The webbing is placed in or on the wound. Thewound is either a primary serous secreting wound or is secondarilyprovided with a physiological solution, such as 0.9% sodium chloridesolution, infused externally. Because the webbing is resorbed into thewound during the healing process, there is no need for its removalduring healing or after the wound has healed.

The fiber density can be freely adjusted during the webbing compactionprocess and is variable depending upon the nature and depth of thewound. In a preferred embodiment of the present invention, a webbing isapplied in or on a wound that is about 1-20 mm in depth, preferablyabout 2-12 mm, dependent mainly upon the thickness of the epidermis. Inother embodiments, the webbing is applied to a wound larger than about20 mm. Thus, the tissue guiding effect of the webbing is also working inlarger wound extensions that is in wounds larger than about 20 mm.

Moreover, by varying the production parameters of the continuous fibersand the webbings (for example, varying the residue(s) X in SiX₄,reaction conditions for the hydrolytic condensation, or the ratio ofnon-polymerized OH-groups, and the like; see DE-C 196 09 551), it ispossible to adjust the resorption rate of the fiber and consequently theresorption rate of the webbing and to adapt them to the conditions ofthe wound. Thus, it is feasible to adjust the resorption rate, forexample, from about 3 to about 180 days depending upon requirements,with the interval being upwardly extendable as seamlessly as desired.

It is possible to control the resorption rate of the webbing and toadapt it to the moist conditions in the wound by varying the number ofOH-groups in the fibers, respectively in the webbing, or by addingmorphogenic factors (healing accelerators, as described further below).Morphogenic factors useful in the compositions and methods of thepresent invention include, but are not limited to, for example, asteroid, a cytokine, an interleukin, a bone morphogenetic protein, anantibody, TNF-α, TGF-β½, IGF, PDGF, and EGF. The morphogenic factors canbe bonded to the fibers (within the webbing) either chemically viaOH-groups or physically by way of physical resorption on the extremelylarge, highly hydrophilic surface. Thus, in a preferred embodiment ofthe present invention, a functional OH-group is present on every fifthto tenth Si-atom. By “functional OH-group” herein is meant an openreaction site in the form of an OH-group to which another compound canbe coupled to the webbing via hydrogen bridges or condensation. In oneembodiment of the present invention, the compound that is coupled to afunctional OH-group of a webbing is a medication, which is then laterreleased incrementally into the wound (drug release). A medicationuseful for the methods and compositions of the present inventioninclude, but are not limited to, for example, an antibiotic, anantimycotic and other drugs having a local or systemic effect. Otheruseful compounds that can be coupled to the webbing in a similar way arenucleotides, amino acids and polymers thereof as described furtherherein. Resorption rates fluctuate at approximately 30 days.

Degradation products (SiO₂ and SiO(OH) as nano-particles) typically areabout 0.5-1 nm in diameter. A precise structure clarification isobtained using Si-solid state NMR, in particular by measuring the Q4mode.

In a preferred embodiment of the present invention, the pressure appliedin the spinning process is from about 1 bar to about 10 bar (10⁵-10⁶Pa), preferably from about 2 bar to 3 bar.

Rates of reaction in the spinning process are preferably from about 20 sto about 60 s.

Temperatures applied to the spinning process are preferably maintainedat from about 15° C. to about 23° C., and particularly preferred atabout 20° C.

An unexpected and surprising finding was that, most likely as a resultof the fiber geometry, an acceleration in the healing of the wound(tissue guiding) is achieved. In this process the two-andthree-dimensionally arranged, highly hydrophilic gel fibers function asa scaffolding to which the proliferating cells are able to adhere and toform a localized mostly collagen matrix. The chemical environment of thefibers is nearly pH neutral (pH 7.0±0.2) and no organic decompositionproducts are formed. Thus, no antigenic reaction or irritation in thenewly generating cells is observed. Rather, the wound healing process iscontinuously stimulated physiologically, because of the accumulation ofthe aforementioned morphogenic factors some of which are also secretedfrom the wound to a certain extent. In contrast to organically derivedgel-like and viscous matrix materials, such as collagen, hyaluronicacid, and fibrin, there is no potential risk of infection in the case ofanorganic fibers with known (HIV, HBV, BSE, prions) and to date unknownsources of infection. In addition, material parameters may be veryprecisely defined and adjusted where anorganic materials are involved.This enhances considerably the quality and property profile of thecompositions of the present invention as compared to organic materials.

In a preferred embodiment of the present invention, the webbing ismanufactured in a saturated alcohol solution as described herein. Hence,the webbing is sterile. The size of a webbing may be variously selectedand is adaptable to the dimensions of currently available wound dressingpads. Preferably, the size of a webbing is 10 cm×10 cm, 5 cm×5 cm or 2.5cm×2.5 cm. Other sizes are freely selectable as well and may be chosenbased on the size of the wound.

A webbing of the present invention can be suitably stored in a varietyof ways. For example, the webbing is packed in a sterile and denselymanner (e.g. in aluminum) and stored or dispatched for futureprocessing. A supplemental depot, such as cotton impregnated withalcohol may also be added to the sterile packaging to maintain thesaturated alcohol atmosphere.

As an alternative for storing, the webbing is directly processed to forma multilayer bandage (see, FIG. 1), that is, it can be bonded to a waterimpermeable (water-impervious) or semi-permeable membrane. The membrane,referred to herein also as a first membrane, may be an adhesive plaster(adhesive bandage). The membrane may also comprise a polyurethane orpolyester film. In one embodiment of the present invention, the firstmembrane has adhesive properties and is referred to as adhesive plaster.The first membrane or adhesive plaster is indicated as 3 in FIG. 1.

During the entire preparation and production periods (from theproduction of the fibers to the placement of the webbing in or on thewound), the fibers and webbings are preferably maintained in a saturatedalcohol-atmosphere, in order to prevent ongoing condensation of thesilicon laden fibrous material and a resultant loss of biodegradabilityof the fibers. This is accomplished, for example, by means of aso-called in-line production process in which production proceeds withina saturated alcohol atmosphere until the final product is obtained. Thisprovides the added advantage that once the final webbing or multilayerbandage is produced, no sterilization (for example, a gammasterilization) is required.

1. Fiber Characteristics

A fiber of the present invention has several advantages overconventional biodegradable and/or bioresorbable biomaterials and can bedistinguished from those by at least four features or characteristics.First, a fiber of the present invention allows for improved celladhesion (adherence of cells to the fiber). Second, a fiber of thepresent invention facilitates cell proliferation (multiplication ofcells). Third, a fiber of the present invention maintains its form andstability. Fourth, a fiber of the present invention maintains thelong-term cell proliferation and cell metabolism.

a) Enhanced Cell Adhesion

The distinctive geometry and morphology of the fiber of the presentinvention make possible, without exception a more rapid initializationand qualitatively enhanced adhesion of cells to the surface of thefiber, as compared to conventional bioresorbable materials, such aspolyglycol acid (PGA), alginates and collagens (FIG. 4). This leads to amore rapid and safer dispersion and outgrowth of cells along the fiberssituated in the wound into all regions of the wound. In addition, havingcells that adhere to the fibers also favors a reliable dispersion ofnewly formed cells distant to the fiber (cell compound proliferation).This advantageous property of the fiber of the present invention can bedemonstrated by scanning-electron-microscopy (SEM), in histological andimmunohistological studies and by confocal microscopy.

b) Accelerated Cell Proliferation

Unlike conventional biodegradable/bioresorbable materials, thedistinctive geometry and morphology of a fiber of the present inventionallows for cell proliferation that is more rapid, has an earlier onset,is accelerated and enhanced and is of longer duration or maintenance.This property furthers the advantages cited above with respect to usingthe fiber's characteristics to facilitate a more rapid and qualitativelyenhanced adhesion of cells to the surface of the fiber.

The metabolic activity of the cells can be measured using thealamarBlue™ Assay (Biosource International, Inc., Camarillo, Calif.,USA; see also, Ahmed et al., J. Immunol. Meth. 170:211-224 (1994); Backet al., J. Neurosci. Methods 91(1-2):47-54 (1999); Collins et al.,Antimicrobial Agents and Chemotherapy 41(5):1004-1009 (1997);Desaulniers et al., Toxicol. In Vitro 12:409-422 (1998); Lelkes et al.,In Vitro Cell. Dev. Biol-Animal 33:344-351 (1997); Shahan et al., J.Immunol. Meth. 175:181-187 (1994)). The alamarBlue™ Assay(alamarBlue™—Reduction) is briefly described. The internal environmentof proliferating cells is more reduced than that of non-proliferatingcells. Specifically, the ratios of NADPH/NADP, FADH/FAD, FMNH/FMN, andNADH/NAD increase during proliferation. Compounds such as alamarBlue™,which can be reduced by these metabolic intermediates, can be used tomonitor cell proliferation. The oxidation-reduction potential ofalamarBlue™ is +380 mV at pH 7.0, 25° C. alamarBlue™, therefore, can bereduced by NADPH (Eo=−320 mV), FADH (Eo=220 mV) FMNH (Eo=−210 mV), NADH(Eo=−320 mV), as well as the cytochromes Eo=290 mV to +80 mV). AsalamarBlue™ accepts electrons from these compounds, it changes from theoxidized indigo blue, non-fluorescing state to the reduced fluorescentpink state. Proliferation can then be monitored spectrophotometricallyeither by color measurement or fluorescence.

The metabolic activity of the cells as determined by this alamarBlue™Assay as a reference parameter for cell proliferation and cellularactivity, is significantly increased after a short to mid-range periodof time of 1, 2 and 4 weeks, as compared with conventional materialssuch as PGA and collagen (FIG. 6). The ratio of cell metabolic activitywith a PGA matrix, a collagen matrix or a SiX₄ matrix (fiber of thepresent invention) is 1:5:11 (1 week), 2.5 11:6 (2 weeks) and 1.2:0.8:6(4 weeks). Initially, (after 24 hours) the ratio was only 1:4.5:4,however. This shows that the advantages of the fiber of the presentinvention become apparent after a relatively lengthy time period of atleast one week, more so by 4 weeks.

c) Maintenance of Fiber Shape and Stability

SEM analysis, and histological and macroscopic studies confirmed that afiber of the present invention, unlike conventional bioresorbablematerials, allows for long-term maintenance of the three-dimensionalshape of the fiber and a delayed (slow) contraction of thethree-dimensional fiber configuration. The fiber geometry and morphologyremain largely intact. Conventional materials such as PGA and collagenshrink (sinter) over a period of 4 weeks by a factor of 4 or 6 and insome cases, also lose their shape. In contrast, a fiber of the presentinvention fully retains its shape and stability over the same timeperiod. This phenomenon is illustrated in FIG. 5. This fact ensures astable build-up of newly formed tissue and it also guarantees adequatediffusion of nutrients and metabolic products even in the case of largewounds.

In addition, unlike materials with less structural stability known inthe prior art and used for this purpose such as PGA or collagen, thisfact also enables and promotes the growth of new vessels. Thus, newvessel and tissue growth in large wounds and the healing thereof, ismade possible for the first time using a fiber of the present invention.

In this regard, an important aspect is the shape stability of the fiberof the present invention, especially in the area of the skin, which hasa mechanical stabilizing effect. Using the multilayer bandage of thepresent invention, the newly formed tissue is adequately supplied withnutrients. Supplying nutrients occurs not only by diffusion, but also bydirect transport of the nutrients through the newly formed vessels andtissues in the open-pored webbing. With regard to shape retaining of thefiber the positive characteristics described for cell proliferation,cell adhesion are adding to this. Maintenance of fiber shape andstability was displayed using the following analytical tools:scanning-electron microscope (SEM), histology and macroscopy

d) Long-Term Maintenance of Cell Proliferation and Cell Metabolism

Unlike conventional bioresorbable biomaterials, the distinctive geometryand morphology of a fiber of the present invention facilitatesmaintenance of cell proliferation over a long period of time therebyachieving reliable tissue build-up and regeneration. Cellular metabolicactivity, determined using the alamarBlue™ Assay as a referenceparameter for cell proliferation and cellular activity, is superiorafter a 4 week period using the SiX₄ fiber of the present invention, ascompared to conventional biomaterials such as PGA and collagen. Theratio for collagen:PGA:SiX₄ is 1:1.5:12 (FIG. 6).

B. Multilayer Bandages

A typical multilayer bandage in accordance with the present invention,placed in or on a wound, is shown in FIG. 1. However, other multilayerbandages are also contemplated within the scope of the present inventionand these are presented below.

In a preferred embodiment of the present invention, a multilayer bandagecomprises (i) a webbing (shown schematically as 1 in FIG. 1), (ii) afirst membrane (shown schematically as 3 in FIG. 1), and (iii) a secondmembrane (shown schematically as 2 in FIG. 1).

In one embodiment of the present invention, the first membrane (3)comprises an adhesive membrane or an adhesive film. The first membrane(3) is then also referred to as an adhesive plaster or adhesive bandage.In this embodiment, the first membrane (3) or adhesive plasterrepresents a dressing. In another embodiment, the first membrane (3) isa simple, water impervious or semi permeable membrane or film. Addingthe second membrane (2) prevents the webbing (1) from being removed fromthe wound (shown schematically as 4 in FIG. 1) when detaching orchanging the outer-disposed first membrane (3) or adhesive plaster. Thefirst membrane (or adhesive plaster) (3) ensures that by using themultilayer bandage of the present invention, the wound (4) is securelysealed off to the surrounding environment.

The second membrane (2) is placed on the webbing (1), that is, betweenthe webbing (1) and the first membrane (3). According to one embodimentof the present invention, the second membrane (2) is not tightlyattached with the webbing (1) nor with the first membrane or adhesiveplaster (3). Still, it is possible to form a tight attachment betweenthe second membrane (2) and the first membrane or adhesive plaster (3).Here it is essential that when removing the first membrane or adhesiveplaster (3), no portion of the webbing (1) and the newly generatedtissue are [ ] removed. The second membrane (2) may also be attached tothe webbing (1). The attachment of the second membrane (2) to webbing(1) is achieved, for example, by means of hydrogen bridges.

The second membrane (2) may comprise a water-soluble polymer (forexample, any polymer that does not bond or stick to the webbing).Preferably a water-soluble polymer of the second membrane (2) iscarboxymethylcellulose (CMC). Here, the choice of polymers is notcrucial (one may feasibly employ water-soluble collagens or fibringels), since the second membrane (2) simply ensures that the adhesivemembrane or film of the first membrane or adhesive plaster (3) does notadhere to the webbing (1). This embodiment is shown in FIG. 1.

In another embodiment of the present invention, the multilayer bandagedoes not comprise the second membrane (2). In this embodiment, thesecond membrane (2) is dispensable, insofar as a dressing is used thatdoes not adhere to the wound and functions additionally like a secondmembrane and/or renders the latter unnecessary. Dressings of the typethat do not adhere to wounds comprise alginates (in compress form or astamponades), collagen sponges, polyurethane foams and foam pads,hydrocolloids, hydrogels and hydropolymers. In this case, the firstmembrane (or adhesive plaster) (3), in order to seal off the wound asshown in FIG. 1, is fastened by means of an adhesive (on the undamagedskin tissue surrounding the wound). Preferred adhesives for the methodsand compositions of the present invention include, but are not limitedto, for example, poly-acylate adhesive, (India) rubber adhesive, andsynthetic (India) rubber adhesives manufactured by a hot-melt method asknown in the art.

In yet another embodiment of the present invention, the multilayerbandage comprises a dressing. A dressing used in the methods andcompositions of the present invention seals off the wound to thesurrounding environment. The dressing can be applied to the webbing (1),for example, on top of the webbing (1). Preferably, the dressing doesnot adhere to the wound (4) (and thus again functions like a secondmembrane (2) and/or renders the latter unnecessary), but still hasadhesive properties and thereby seals the wound (4) off from theoutside. In a preferred embodiment of the present invention, thedressing is a foam bandage, in particular a polyurethane foam bandage,because such foam bandages have a high fluid storage capacity (Bello andPhillips, JAMA 283(6):716-718 (2000); Degreef, Dermatol Clin16(2):365-375 (1998); Findlay, Am Fam Physician 54(5):1519-1528 (1996);Habif, Clinical Derm, Moshby, pp. 810-813 (1996); Knapp, Ped Clin N Am46(6):1201-1213 (1999); Krasner, Prevention Management Pressure Ulcers,(1995); Lewis, Med-Surg Nursing, Moshby, pp 199-200; Lueckenotte,Gerontologic Nurs, Moshby, pp. 800-807 (1996); PUGP, Am Fam Physician,51(5):1207-1222 (1995); PUGP, Pressure Ulcer Treatment, AHCPR 95-0653(1994); Way, Current Surgical, Lange, pp. 95-108 (1991)). Foam bandagesparticularly useful for the methods and compositions of the presentinvention include, but are not limited to, for example, foam dressingfrom 3M, Silastic from Dow Corning (distributed by Calmic MedicalDivision), Allevyn from Smith and Nephew, und Lyofoam from SetonHealthcare Group plc.

According to still another embodiment of the present invention, it ispossible to omit completely (without substitution) the second membrane(2) when the first membrane (3) (in this case not necessarily adhesive)is applied directly to the webbing (1). In this embodiment, the adhesivemembrane or film of the first membrane (or adhesive plaster) (3) formsan adhesive bond exclusively with the skin tissue on the perimeter ofthe wound (4), thereby making it impossible for the first membrane (3)to bond with the webbing (1). This is achieved, for example, by applyingto the skin tissue on the wound periphery an adhesive, for example,Leukospray™ (Baiersdorf), prior to the occlusion process. In such case,the first membrane (3) is itself non-adhesive and is thus moreaccurately characterized as a first membrane (3), rather than adhesiveplaster or adhesive bandage. Alternatively, this can be achieved byselecting or cutting to size the first membrane or adhesive plaster (3)to correspond to the size of the wound (4). In this case, the adhesiveplaster is adhesive only at those points not directly contacting thewound (4).

According to the present invention the first membrane (3) is composed ofa water-impervious film made of at least one water-insoluble polymer.The water-insoluble polymer, for example, can be polypropylene (PP),polyvinylchloride (PVC) or polyurethane (PU). In another embodiment ofthe present invention, the first membrane (3) further comprises anadhesive conventionally used in bandage technology, which preferablyexhibits particularly strong skin tissue compatibility. Adhesivesparticularly useful for the methods and compositions of the presentinvention include, but are not limited to, for example, polyacrylateadhesives and synthetic (India) rubber adhesives. These arehypoallergenic and have strong tissue compatibility. The adhesive can beapplied to the water-impervious film immediately upon or prior toassembly of the multilayer bandage. However, it can also be applied orsprayed by the user, as described above, to an area on the perimeter ofthe wound, or to the membrane or film.

A water-impervious adhesive plaster (3) or water-impervious firstmembrane (3) ensures that no moisture can evaporate outwardly, therebymaintaining permanently a moist wound environment which aids in theresorption of the webbing fibers. Resorption of the fibers also causessubstances potentially bound to the fibers to be released, that is, arelease and accumulation of ions (for example, Ag-ions), medications(for example, an antibiotic, an antimycotic, or a corticoid) ormorphogenic factors. Morphogenic factors (also referred to asmorphogenes), to be used in the methods and compositions of the presentinvention include, but are not limited to, for example, a steroid, acytokine, an interleukin, a bone morphogenetic protein (BMP), anantibody, TGF-β, IGF, TNF-α, PDGF, and EGF. Morphogenic factors are alsoformed to a certain extent by the organism during wound healing.Generally, morphogenic factors exert a favorable influence on, and areindispensable for proper wound healing.

The water solubility of the polymer of the second membrane (2) makes iteasy to loosen the membrane (when present) after a certain period ofexposure. This is possible because the hydrous wound exudates graduallyloosens the webbing (1) from the second membrane (2) so as not to resultin damage to the tissue as the second membrane (2) is lifted of. Toreduce the risk of infection, polymers doped with silver areadvantageously employed as a second membrane (2).

In the case of particularly large wounds (>10 cm²) a floating bandage isexpedient, because under certain circumstance the adhesive forces of asecond membrane (2) to the webbing (1) would become too great. In suchcases it is possible to use a separation medium in the form of hydrogelsas a thin (<5 mm) floating layer.

If needed additional bandage material (for example, bandage gauze) orother materials, such as for padding or protection may be applied to themultilayer bandage as described in its various embodiments according tothe present invention. Thus, within the scope of the present disclosurea distinction is made between dressing and bandage material. In oneembodiment of the present invention, dressing is a component of themultilayer bandage. Bandage material is basically used as a pad forprotection of the wound. There is no direct contact between bandagematerial and webbing, i.e., between bandage material and thebioresorbable fibers.

Prior to placing the webbing (1) in or on a wound (4) or furtherprocessing it to form a multilayer bandage (i.e. after manufacture, instorage or during transport, be it as webbing (1) only or forming amultilayer bandage), it is preferable to insulate with a thick membranethe surface of the webbing that is subsequently in contact with thewound. This membrane serves to prevent leakage of the alcohol. Thismembrane can easily be removed by the user, optionally directly prior toapplication on the wound. It is important to note that alcohol, asdiscussed above, stabilizes the sterility and chemistry of the fibers,but it is extremely painful when brought in contact with the wound.Therefore, in accordance with another preferred embodiment of thepresent invention, physiological saline may be used as a medium.Alternatively, it is possible to evaporate or rinse out the alcoholprior to use.

Typical dressings to which the webbing may be fitted include, but arenot limited to the following products (by trademark): DermaplastFilm/Active™ and Hydractive™; Hydrofilm PlusTM™; Hydrocoll™ (Hartmann);Comfeel (-Plus)™, Biatain™, Seasorb™, Contreet™ (Coloplast), CutinovaHydro™, Acticoat™, and Allevyn™ (Smith & Nephew).

The webbing (1) may also be combined with products currently on themarket in all their variations, for example with the following Smith &Nephew products: Hydrogel-bandages™, IntraSite ConformableTM®, IntraSiteGelTM™, hydro-selective wound dressings, Cutinova Hydro™ (for example,hydro cellular foam wound dressings), Allevyn™ product group (forexample, alginate, antimicrobial wound dressings, enzymatic debridement,odor-resorbing bandages, post-operative-bandages), Cutiplast Steril™,Hansapor Steril™, OpSite Post-OpTM®, Primapore™ (for example, specialtybandages), Allevyn Tracheostomy™, Cavi-Care™, and EXU-DRY™.

Thus, the webbing (1) may be combined, for example, with polyurethane orPVA-sponge dressings to enhance resorbence in the case of heavilyexudating wounds. The aforementioned advantages of the present inventionare particularly evident in the use of vacuum systems (for example,V.A.C™), for example in the treatment of septic wounds and whereantibiotic flushing is required. In addition, the webbing may becombined with the alginate-tamponade described above as a covering foruse in hydrocolloid wound dressings.

The shape of the multilayer-bandage may vary depending on the locationof the wound, as well as its shape and size, to thereby obtain amaximally precise fit with the anatomy of the wound. One optionalbandage shape is the butterfly bandage for application in the analregion.

In one embodiment of the present invention, the aforementionedmultilayer bandage has the following structure: (i) a webbing (1) forplacement in direct contact with a wound (4), and (ii) a first membrane(3) which is water impervious and comprises at least one water insolublepolymer, wherein the first membrane (3) is an adhesive plaster andcomprises an adhesive portion that bonds with skin tissue at a woundperiphery.

In another embodiment the first membrane (3) does not comprises anadhesive portion and bonds with an adhesive which is applied to the skintissue at said wound periphery, and wherein a loose, frangible adhesivebond or no adhesive bond at all exists between the first membrane (3)and the webbing (1). The term “loose, frangible adhesive bond” means anadhesive bond that is capable of being broken easily but does notnecessarily imply an inherent weakness.

A preferred multilayer bandage of the present invention is one whereinthe first membrane (3) is as described herein and wherein the webbing(1) comprises a biologically degradable and/or resorbable fiberstructure. This fiber structure is obtained, for example, by drawingfibers from a spun composition. A spun composition, as described herein,comprises one or more partially or completely hydrolytically condensedsilicon compounds that are obtained by hydrolytic condensation ofmonomers of the general formula SiX₄. SiX₄ is a tetravalent compoundcomprising residues X₁, X₂, X₃, and X₄. In one embodiment of the presentinvention, residues X₁, X₂, X₃, and X₄ are identical. In anotherembodiment of the present invention, residues X₁, X₂, X₃, and X₄ aredifferent. In a preferred embodiment of the present invention, residuesX₁, X₂, X₃, and X₄ are independently selected from the group consistingof hydroxyl, hydrogen, halogen, amino, alkoxy, alkyloxy, alkylcarbonyland alkoxycarbonyl. As used herein, the term “halogen” refers to theelements including fluorine (F), chlorine (Cl), bromine (Br) and iodine(I). The term “alkoxy” refers to alkyl radicals attached to theremainder of a molecule by an oxygen, e.g., ethoxy, methoxy, orn-propoxy. The term “alkoxy” also refers to a heteroalkyl that containsone or more oxygen heteroatoms.

In yet another embodiment two residues, for example X₁ and X₂ areidentical and two residues, for example X₃ and X₄ are different. Inanother embodiment, three residues, for example X₁, X₂, and X₃ areidentical and one residue, for example X₄ is different.

In another embodiment, residues X₁, X₂, X₃, and X₄ are derived from analkyl and can be interrupted by one or more oxygen atoms, sulfur atomsor amino groups. As used herein, the term “alkyl” refers to a straightor branched chain hydrocarbon radical, and can include di-andmultivalent radicals, having the number of carbon atoms designated (i.e.C₁-C₁₀ means one to ten carbons). Examples of saturated hydrocarbonradicals include groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

A preferred multilayer bandage of the present invention is a multilayerbandage wherein residues X₁, X₂, X₃, and X₄ of SiX₄ are identical andare ethyl.

1. Multilayer Bandages Wherein the Hydrolytic Condensation Occurs in thePresence of Organic Compounds

Hydrolytic condensation as described herein can be performed in thepresence of several organic compounds, preferably nucleotides or aminoacids and polymers thereof. The presence of the amino acid(s), and/orpeptide(s) and/or DNA molecules or DNA fragments leads to theirincorporation into the fibers. In one embodiment of the presentinvention, incorporation of these organic compounds is through covalentbonds. In another embodiment, incorporation is by non-covalent bonds.

Once the multilayer bandage is applied to the wound the amino acid(s),peptide(s), DNA molecule(s) or DNA fragments are released from thebandage at a rate which corresponds to the rate of degradation of thefibers. The amount of amino acid(s), peptide(s), DNA molecule(s) or DNAfragments released is determined by the amount of amino acid(s),peptide(s), DNA molecule(s) or DNA fragments incorporated into thefibers while the rate of release from the fibers is determined by therate of degradation of the fibers.

Cell adhesion, an attribute of the fiber as described above, enables toa significant extent the take up of the amino acid(s), peptide(s), DNAmolecule(s) and/or DNA fragment(s) into the proliferating cells. Inparticular this take-up ensures that the cells can be directlyinfluenced by the peptide(s) or by the genetic information encoded bythe nucleic acid. This is especially important and of use where woundswith reduced regional or even systemic metabolic rates are concerned,because it ensures, for example, an external supply to the wound regionof amino acids necessary in cell metabolic activity, making woundhealing feasible.

a) Multilayer Bandages wherein the Hydrolytic Condensation Occurs in thePresence of One or More Amino Acids or Peptides

In a preferred embodiment of the present invention, the multilayerbandage is a multilayer bandage wherein the hydrolytic condensationoccurs in the presence of one or more amino acids. In one preferredembodiment of this multilayer bandage, the residues X in the formulaSiX₄ are identical and are ethyl.

The term “amino acid” refers to naturally occurring and synthetic aminoacids, as well as amino acid analogs and amino acid mimetics thatfunction similarly to the naturally occurring amino acids. Naturallyoccurring amino acids are those encoded by the genetic code, as well asthose amino acids that are later modified, e.g., hydroxyproline,Y-carboxyglutamate, and O-phosphoserine. “Amino acid analog” refers to acompound that has the same basic chemical structure as a naturallyoccurring amino acid, e.g., an a carbon that is bound to a hydrogen, acarboxyl group, an amino group, and an R group, e.g., homoserine,norleucine, methionine sulfoxide, methionine methyl sulfonium. Suchanalogs may have modified R groups (e.g., norleucine) or modifiedpeptide backbones, but retain the same basic chemical structure as anaturally occurring amino acid. “Amino acid mimetic” refers to achemical compound that has a structure that is different from thegeneral chemical structure of an amino acid, but that functionssimilarly to a naturally occurring amino acid.

Amino acids may be referred to herein by either their commonly knownthree letter symbols or by the one-letter symbols recommended by theIUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise,may be referred to by their commonly accepted single-letter codes.

Another preferred multilayer bandage of the present invention is amultilayer bandage wherein the hydrolytic condensation occurs in thepresence of one or more peptides. In one preferred embodiment of thismultilayer bandage, the residues X in the formula SiX₄ are identical andare ethyl.

The terms “peptide,” “polypeptide” and “protein” are usedinterchangeably herein to refer to a polymer of amino acid residues. Theterms apply to amino acid polymers in which one or more amino acidresidue is an artificial chemical mimetic of a corresponding naturallyoccurring amino acid, as well as to naturally occurring amino acidpolymers, those containing modified residues, and non-naturallyoccurring amino acid polymer.

Macromolecular structures such as polypeptide structures can bedescribed in terms of various levels of organization. For a generaldiscussion of this organization, see, e.g., Alberts et al., MolecularBiology of the Cell (3^(rd) ed., 1994) and Cantor & Schimmel,Biophysical Chemistry Part I: The Conformation of BiologicalMacromolecules (1980). “Primary structure” refers to the amino acidsequence of a particular peptide. “Secondary structure” refers tolocally ordered, three dimensional structures within a polypeptide.These structures are commonly known as domains. Domains are portions ofa polypeptide that often form a compact unit of the polypeptide and aretypically 25 to approximately 500 amino acids long. Typical domains aremade up of sections of lesser organization such as stretches of β-sheetand α-helices. “Tertiary structure” refers to the complete threedimensional structure of a polypeptide monomer. “Quaternary structure”refers to the three dimensional structure formed by independent tertiaryunits, usually by noncovalent association.

In a preferred embodiment of the present invention, the hydrolyticcondensation occurs in the presence of morphogenic factors describedabove.

b) Multilayer Bandages wherein the Hydrolytic Condensation Occurs in thePresence of One or More Nucleotides, Nucleic Acids, Oligonucleotides, orPolynucleotides

Another preferred multilayer bandage of the present invention is amultilayer bandage wherein the hydrolytic condensation occurs in thepresence of one or more nucleotides, nucleic acids, oligonucleotides,polynucleotides, DNA molecules or DNA fragments. In one preferredembodiment of this multilayer bandage, the residues X in the formulaSiX₄ are identical and are ethyl.

“Nucleic acid” or “oligonucleotide” or “polynucleotide” or grammaticalequivalents used herein means at least two nucleotides covalently linkedtogether. Oligonucleotides are typically from about 5, 6, 7, 8, 9, 10,12, 15, 25, 30, 40, 50 or more nucleotides in length, up to about 100nucleotides in length. Nucleic acids and polynucleotides are polymers ofany length, including longer lengths, e.g., 200, 300, 500, 1000, 2000,3000, 5000, 7000, 10,000 nucleotides, etc. A nucleic acid will generallycontain phosphodiester bonds, although in some cases, nucleic acidanalogs are included that may have alternate backbones, comprising,e.g., phosphoramidate, phosphorothioate, phosphorodithioate, orO-methylphophoroamidite linkages (see, Eckstein, Oligonucleotides andAnalogues: A Practical Approach, Oxford University Press); and peptidenucleic acid backbones and linkages. Other analog nucleic acids includethose with positive backbones; non-ionic backbones, and non-ribosebackbones, including those described in U.S. Pat. Nos. 5,235,033 and5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, CarbohydrateModifications in Antisense Research, Sanghui & Cook, eds. Nucleic acidscontaining one or more carbocyclic sugars are also included within onedefinition of nucleic acids. Modifications of the ribose-phosphatebackbone may be done for a variety of reasons, e.g. to increase thestability and half-life of such molecules in physiological environments.Mixtures of naturally occurring nucleic acids and analogs can be made;alternatively, mixtures of different nucleic acid analogs, and mixturesof naturally occurring nucleic acids and analogs may be made.

A variety of references disclose such nucleic acid analogs, including,for example, phosphoramidate (Beaucage et al., Tetrahedron 49(10):1925(1993) and references therein; Letsinger, J. Org. Chem. 35:3800 (1970);Sprinzl et al., Eur. J. Biochem. 81:579 (1977); Letsinger et al., Nucl.Acids Res. 14:3487 (1986); Sawai et al., Chem. Lett. 805 (1984),Letsinger et al., J. Am. Chem. Soc. 110:4470 (1988); and Pauwels et al.,Chemica Scripta 26:141 91986)), phosphorothioate (Mag et al., NucleicAcids Res. 19:1437 (1991); and U.S. Pat. No. 5,644,048),phosphorodithioate (Briu et al., J. Am. Chem. Soc. 111:2321 (1989), 0methylphophoroamidite linkages (see, Eckstein, Oligonucleotides andAnalogues: A Practical Approach, Oxford University Press), and peptidenucleic acid backbones and linkages (see, Egholm, J. Am. Chem. Soc.114:1895 (1992); Meier et al., Chem. Int. Ed. Engl. 31:1008 (1992);Nielsen, Nature 365:566 (1993); Carlsson et al., Nature 380:207 (1996),all of which are incorporated by reference). Other analog nucleic acidsinclude those with positive backbones (Denpcy et al., Proc. Natl. Acad.Sci. USA 92:6097 (1995); non ionic backbones (U.S. Pat. Nos. 5,386,023,5,637,684, 5,602,240, 5,216,141 and 4,469,863; Kiedrowshi et al., Angew.Chem. Intl. Ed. English 30:423 (1991); Letsinger et al., J. Am. Chem.Soc. 110:4470(1988); Letsinger et al., Nucleoside & Nucleotide13:1597(1994); Chapters 2 and 3, ASC Symposium Series 580, “CarbohydrateModifications in Antisense Research”, Ed. Y. S. Sanghui and P. Dan Cook;Mesmaeker et al., Bioorganic & Medicinal Chem. Lett. 4:395 (1994); Jeffset al., J. Biomolecular NMR 34:17 (1994); Tetrahedron Lett. 37:743(1996)) and non ribose backbones, including those described in U.S. Pat.Nos. 5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series580, “Carbohydrate Modifications in Antisense Research”, Ed. Y. S.Sanghui and P. Dan Cook. Nucleic acids containing one or morecarbocyclic sugars are also included within one definition of nucleicacids (see, Jenkins et al., Chem. Soc. Rev. pp 169 176 (1995)). Severalnucleic acid analogs are described in Rawls, C & E News Jun. 2, 1997page 35. All of these references are hereby expressly incorporated byreference.

Other analogs include peptide nucleic acids (PNA) which are peptidenucleic acid analogs. These backbones are substantially non-ionic underneutral conditions, in contrast to the highly charged phosphodiesterbackbone of naturally occurring nucleic acids. Typically, PNAs are notdegraded by cellular enzymes, and thus can be more stable.

The nucleic acids may be single stranded or double stranded, or containportions of both double stranded or single stranded sequences. Thenucleic acid may be DNA, both genomic and cDNA, RNA or a hybrid, wherethe nucleic acid may contain combinations of deoxyribo-andribo-nucleotides, and combinations of bases, including uracil, adenine,thymine, cytosine, guanine, inosine, xanthine hypoxanthine, isocytosine,isoguanine, etc. RNA typically refers to a naturally occurring RNA,e.g., a pre-mRNA, hnRNA, or mRNA. The nucleic acid may be a naturallyoccurring nucleic acid or may be synthesized de novo either chemicallyor by using recombinant DNA methodology.

In a preferred embodiment of the present invention, the hydrolyticcondensation occurs in the presence of a nucleic acid encoding amorphogenic factor described above.

C. Kits

The invention also provides kits that can be used for accelerated woundhealing as described herein. In a preferred embodiment of the presentinvention, a kit comprises a multilayer bandage embracing the specificsas outlined herein, wherein the multilayer bandage is used foraccelerated wound healing. The kit may further comprise instructions forusing the compositions of the present invention in accelerating woundhealing.

Further, kits are provided comprising compositions described herein thatallow the user to practice the methods of the invention. As indicatedabove, the kits may include instructional materials containingdirections (e.g., protocols) for the practice of this invention. Whilethe instructional materials typically comprise written or printedmaterials they are not limited to such. Any medium capable of storingsuch instructions and communicating them to an user is contemplated bythis invention. Such media include, but are not limited to, electronicstorage media (e.g., magnetic discs, tapes, cartridges, chips), opticalmedia (e.g., CD ROM), and the like. Such media may include addresses tointernet sites that provide such instructional materials.

Additional kit embodiments of the present invention include optionalfunctional components that would allow one of ordinary skill in the artto perform any of the method variations described herein.

Although the forgoing invention has been described in some detail by wayof illustration and example for clarity and understanding, it will bereadily apparent to one ordinary skill in the art in light of theteachings of this invention that certain variations, changes,modifications and substitutions of equivalents may be made theretowithout necessarily departing from the spirit and scope of thisinvention. As a result, the embodiments described herein are subject tovarious modifications, changes and the like, with the scope of thisinvention being determined solely by reference to the claims appendedhereto. Those of skill in the art will readily recognize a variety ofnon-critical parameters that could be changed, altered or modified toyield essentially similar results.

While each of the elements of the present invention is described hereinas containing multiple embodiments, it should be understood that, unlessindicated otherwise, each of the embodiments of a given element of thepresent invention is capable of being used with each of the embodimentsof the other elements of the present invention and each such use isintended to form a distinct embodiment of the present invention.

All publications, patents and patent applications cited in thisspecification are herein incorporated in their entireties by referenceas if each individual publication, patent or patent application werespecifically and individually indicated to be incorporated by reference.

1. A wound healing multilayer bandage comprising: (i) a webbing forplacement in direct contact with a wound having a periphery; and (ii) afirst membrane comprising at least one water-insoluble polymer; whereinthe webbing has a biologically degradable or a biologically resorbablefiber structure; wherein the webbing is a spun-bonded webbing; whereinthe webbing comprises at least one partially or completelyhydrolytically condensed silicon compound; wherein the first membrane iswater-impervious or semi-permeable; wherein the first membrane either(a) further comprises an adhesive portion wherein the adhesive portionadheres to skin tissue at the wound periphery or (b) does not comprisean adhesive portion and bonds with an adhesive which is applied to theskin tissue at the wound periphery, wherein the first membrane isconfigured to seal the wound off from a surrounding environment when thefirst membrane is adhered to the skin tissue at the wound periphery orbonded to an adhesive which is applied to the skin tissue at the woundperiphery; and wherein either no bond or a loose, frangible adhesivebond exists between the first membrane and the webbing.
 2. Themultilayer bandage according to claim 1, wherein the water-insolublepolymer is selected from the group consisting of polypropylene,polyvinylchloride and polyurethane.
 3. The multilayer bandage accordingto claim 1, wherein the first membrane is a self-adhesive hydropolymer.4. The multilayer bandage according to claim 1, wherein the webbing is afibrous webbing.
 5. The multilayer bandage according to claim 1, whereinthe silicon compound comprises a monomer of the formula SiX₄ whereinresidues X₁, X₂, X₃, and X₄ are independently selected from the groupconsisting of hydroxyl, hydrogen, halogen, amino, alkoxy, alkyloxy,alkylcarbonyl and alkoxycarbonyl.
 6. The multilayer bandage according toclaim 1, wherein the silicon compound comprises a monomer of the formulaSiX₄ wherein residues X₁, X₂, X₃, and X₄ are derived from an alkyl andcan be interrupted by an oxygen atom, a sulfur atom or an amino groupand wherein residues X₁, X₂, X₃, and X₄ are identical or different. 7.The multilayer bandage according to claim 6, wherein residues X₁, X₂,X₃, and X₄ are ethyl.
 8. The multilayer bandage according to claim 7,wherein the webbing comprises a morphogenic factor selected from thegroup consisting of a steroid, a cytokine, an interleukin, a bonemorphogenetic protein, an antibody, TNF-α, TGF-(β½, IGF, PDGF, and EGF.9. The multilayer bandage according to claim 1, wherein the webbingcomprises an organic compound selected from the group consisting of anucleotide, an amino acid and polymers thereof.
 10. A wound healingmultilayer bandage comprising: (i) a webbing for placement in directcontact with a wound having a periphery; and (ii) a first membranecomprising at least one water-insoluble polymer; wherein the webbing hasa biologically degradable or a biologically resorbable fiber structure;wherein the webbing is a spun-bonded webbing; wherein the webbingcomprises at least one partially or completely hydrolytically condensedsilicon compound; wherein the first membrane is water-impervious;wherein the first membrane either (a) further comprises an adhesiveportion wherein the adhesive portion adheres to skin tissue at the woundperiphery or (b) does not comprise an adhesive portion and bonds with anadhesive which is applied to the skin tissue at the wound periphery,wherein the first membrane is configured to seal the wound off from asurrounding environment when the first membrane is adhered to the skintissue at the wound periphery or bonded to an adhesive which is appliedto the skin tissue at the wound periphery; and wherein either no bond ora loose, frangible adhesive bond exists between the first membrane andthe webbing; and (iii) a second membrane comprising at least onewater-soluble polymer; wherein the second membrane is disposed betweenthe first membrane and the webbing.
 11. The multilayer bandage accordingto claim 10, wherein the water-soluble polymer iscarboxymethylcellulose.
 12. The multilayer bandage according to claim10, wherein a bond exists between the second membrane and the webbingand wherein the bond is a loose, frangible adhesive bond.
 13. Themultilayer bandage according to claim 10, wherein no adhesive bondexists between the second membrane and the webbing.
 14. The multilayerbandage according to claim 10, wherein a bond exists between the firstmembrane and the second membrane and wherein the bond is a loose,frangible adhesive bond or a stable, non-frangible adhesive bond.
 15. Awound healing multilayer bandage comprising: (i) a webbing for placementin direct contact with a wound having a periphery; and (ii) a firstmembrane comprising at least one water-insoluble polymer; wherein thewebbing has a biologically degradable or a biologically resorbable fiberstructure; wherein the webbing is a spun-bonded webbing; wherein thewebbing comprises at least one partially or completely hydrolyticallycondensed silicon compound; wherein the first membrane iswater-impervious; wherein the first membrane either (a) furthercomprises an adhesive portion wherein the adhesive portion adheres toskin tissue at the wound periphery or (b) does not comprise an adhesiveportion and bonds with an adhesive which is applied to the skin tissueat the wound periphery, wherein the first membrane is configured to sealthe wound off from a surrounding environment when the first membrane isadhered to the skin tissue at the wound periphery or bonded to anadhesive which is applied to the skin tissue at the wound periphery; andwherein either no bond or a loose, frangible adhesive bond existsbetween the first membrane and the webbing; and (iii) a dressingselected from the group consisting of an alginate, a collagen sponge, apolyurethane foam, a polyurethane foam pad, a hydrocolloid, a hydrogeland a hydropolymer, and wherein the dressing is disposed between thewebbing and the first membrane.
 16. The multilayer bandage according toclaim 15, wherein a bond exists between the dressing and the webbing andwherein the bond is a loose, frangible adhesive bond.
 17. The multilayerbandage according to claim 15, wherein no adhesive bond exists betweenthe dressing and the webbing.
 18. The multilayer bandage according toclaim 15, wherein a bond exists between the dressing and the firstmembrane and wherein the bond is either a loose, frangible adhesive bondor a stable, non-frangible adhesive bond.
 19. A method for treating awound having a periphery, the method comprising: placing a webbing indirect contact with a wound, wherein the webbing is spun-bonded webbingand has a biologically degradable or a biologically resorbable fiberstructure, wherein the webbing comprises at least one partially orcompletely hydrolytically condensed silicon compound; and applying afirst membrane onto a top side of the webbing, wherein the top side ofthe webbing is located opposite to the wound, wherein the first membraneis water-impervious or semi-permeable such that moisture is preventedfrom evaporating outwardly from the wound through the first membrane,wherein the first membrane comprises at least one water-insolublepolymer, wherein the first membrane either (a) further comprises anadhesive portion wherein the adhesive portion adheres to skin tissue atthe periphery of the wound or (b) does not comprise an adhesive portionand bonds with an adhesive which is applied to the skin tissue at theperiphery of the wound, and further wherein either no bond or a loose,frangible adhesive bond exists between the first membrane and thewebbing.